Mycobacteria have plagued humanity for several millennia by causing major diseases like tuberculosis (TB), leprosy and Buruli ulcer. In terms of disease burden and mortality, TB is incontestably the most important and challenging threat to human health, in part because of the increasing prevalence of primary resistance to the current drugs. There is thus a growing need for new compounds with a novel mode of action (Balganesh, T. S., P. M. Alzari, and S. T. Cole. Trends Pharmacol Sci, 2008. 29(11): p. 576-81.) and these may also find application in treating other mycobacterial diseases. Leprosy is nearing elimination as a public health problem (Britton, W. J. and D. N. Lockwood. Lancet, 2004. 363(9416): p. 1209-19), thanks to the control measures implemented by the World Health Organisation, while the emerging disease, Buruli ulcer, is of growing concern (Demangel, C., T. P. Stinear, and S. T. Cole, Nat Rev Microbiol, 2009. 7(1): p. 50-60).
In the past twenty years, drug resistant tuberculosis has assumed alarming new dimensions. Of concern in the 1990s was the multidrug resistant (MDR) form, where Mycobacterium tuberculosis had acquired resistance to the main front-line drugs isoniazid and rifampicin. There are an estimated 500,000 cases of MDR-TB worldwide of which ˜70,000 occur in Europe (Zignol, M. et al. J Infect Dis, 2006. 194: 479-485; Fears, R., S. Kaufmann, V. Ter Meulen & A. Zumla. Tuberculosis (Edinb) 2010. 90: 182-187).
In the past decade, MDR strains of M. tuberculosis have acquired additional resistance mutations to second line drugs giving rise to extensively drug resistant (XDR) disease. In addition to isoniazid and rifampicin, XDR strains of M. tuberculosis are also resistant to fluoroquinolones and to the injectable aminoglycosides (Jassal, M. & W. R. Bishai. Lancet Infect Dis 2009. 9: 19-30). Over 50 countries have now reported XDR-TB thereby underlining the necessity and importance of finding new drugs to treat both drug-sensitive and drug-resistant TB. In addition to a new mechanism of action, other desirable features required of a new TB drug include high potency, so that treatment duration can be reduced; high specificity, to avoid unwanted side-effects including destruction of the gut flora; and oral administration.
2-Amino substituted 1,3-benzothiazine-4-ones can be used as drugs for the treatment of mycobacterial diseases in humans and mammals. The most active compound available till now is 2-[(2S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothia-zin-4-one (BTZ043) (V. Makarov et al. Science, 2009, 324, 801; M. R. Pasca, et al. Antimicrob. Agents Chemother., 2010, 54, 1616).
Specific 2-amino substituted 1,3-benzothiazine-4-ones are disclosed e.g. in WO 2007/134625 and WO 2009/010163.
In view of this background, it is highly desirable to produce new 2-piperazino substituted 1,3-benzothiazine-4-ones, which not only have high activity against mycobacteria but also display better drug-like properties than previously described so 1,3-benzothiazine-4-ones. The present invention describes a new generation of 1,3-benzothiazine-4-ones with activity against mycobacteria as potential new TB drugs where the 2-amino substitution is represented by N-substituted piperazines.